1. Field of the Invention
The present invention relates to a novel derivative of kojic acid and to its use in a composition for topical application as a depigmenting and/or bleaching agent for skin.
2. Discussion of the Background
Skin color depends on different factors such as the seasons of the year, race, and sex. Skin color is mainly determined by the concentration of melanin produced by the melanocytes. In addition, at different periods in life, certain individuals develop dark and/or colored blemishes on the skin and more especially on the hands, making the skin non-uniform in color. These blemishes may also arise due to a high concentration of melanin in the keratinocytes at the skin surface.
For several years, it has been sought to decrease and/or slow down the production of melanin in order to depigment or bleach the skin by acting on one or more of the points in the intracellular biochemical synthesis of melanin. To achieve this end, various compounds have been tested and used as depigmenting or bleaching agents for human skin.
The mechanism of skin pigmentation, i.e., forming melanin, is particularly complex and is believed to involve the following steps:
Tyrosine.fwdarw.Dopa.fwdarw.Dopaquinone.fwdarw.Dopachrome.fwdarw.Melanin PA1 applying, to human skin, a composition containing a skin depigmenting effective amount of a 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl 2-oxothiazolidine-4-carboxylate compound having the formula (I): ##STR6## or a pharmaceutically acceptable salt thereof. PA1 contacting melanocytes with a melanin production inhibiting effective amount of a 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl 2-oxothiazolidine-4-carboxylate compound having the formula (I): ##STR7## or a pharmaceutically acceptable salt thereof PA1 mixing kojic acid, dissolved in acidic medium, with hydrobromic acid, heating the reaction mixture, cooling it and filtering it; PA1 reacting the bromo derivative obtained with L-2-oxothiazolidine-4-carboxylic acid, in the presence of potassium carbonate; PA1 heating the reaction mixture, cooling it and filtering it.
Tyrosinase is the essential enzyme involved in the above reaction sequence. In particular, tyrosinase is believed to catalyze the reaction for converting tyrosine into dopa (dihydroxyphenylalanine) and the reaction for converting dopa into dopaquinone. Tyrosinase is believed to act only when it is in the mature state, under the action of certain biological factors.
Generally, a substance is recognized as being depigmenting if it acts directly on the viability of the epidermal melanocytes in which melanogenesis takes place and/or if it interferes with one of the steps in the biosynthesis of melanin either by inhibiting one of the enzymes involved in melanogenesis or by becoming intercalated as a structural analogue of one of the chemical compounds in the melanin synthesis chain, described above, whereby the chain is effectively blocked thus ensuring depigmentation.
The substances most commonly used as depigmenting agents in compositions are, for example, vitamin C, vitamin C derivatives, vitamin E derivatives, arbutin, hydroquinone, kojic acid, placental derivatives, and glutathione and its derivatives.
The above compounds are believed to act on the synthesis and/or activity of tyrosinase, the enzyme involved in the synthesis of melanin, or to reduce the amount of melanin formed, or, alternatively, to stimulate the removal of melanin via the keratinocytes. Unfortunately, the compounds are either toxic, in the case of hydroquinone, or unstable in solution, in the case of vitamin C and kojic acid, and are therefore difficult to manufacture, or else they have unpleasant sulfurous odors, for example, glutathione. Consequently, use of the above compounds is limited.
Thus, there is a need for a novel skin-bleaching agent which is at least as effective as the conventional agents but does not have their disadvantages, i.e., one that is stable in a composition, is non-toxic when applied to the skin, and has no unpleasant odor.